PROJECT SUMMARY Cellular immunotherapy has the potential to become the definitive solution for cancer. However, toxic chemotherapy is currently required as preconditioning treatment to impair graft rejection and maintain therapeutic cells in the bloodstream where they can target cancer cells. Chemotherapy is hardly tolerated by frail cancer patients, and it fuels the side effects of immunotherapy such as toxic cytokine releases (CRS) and neuroedemas. AVM Biotechnology (AVM) is working towards a novel safe pre-conditioning regimen, named AVM0703, which could be easily administered to increase efficient delivery of adoptive cellular immunotherapy. AVM0703 induces safe lymphodepletion in only 24 hours, sparing platelets, stem cells and red blood cells. Interestingly, AVM0703 can safely deplete monocytes, known to be a key inducer of CRS. CRS toxicities occur as frequently as 90% with half of them determined as severe. Severe CRS complications can be life threatening if not treated in a timely manner. Levels of IL-6 are elevated during CRS and animal studies have demonstrated that monocytes are the primary source of IL-6. Depletion of IL-6 producing monocytes protected mice from CRS-induced lethality. Unlike chemotherapy, AVM0703 can safely deplete monocytes reducing the risk of CRS and making cellular immunotherapy accessible to high-risk individuals like older/frail patients. AVM0703 mode of action could offer an exemplary preconditioning regimen. To establish feasibility for this product, we propose the following two specific aims. Aim 1. Evaluate the efficacy of AVM0703 as preconditioning for T-cell transfusion in an immunocompetent Multiple Myeloma (MM) mouse model. The level of lymphodepletion, improvement in T cell circulation, and the level of cytotoxicity induced by AVM0703 will be monitored and compared to standard chemotherapy. Finally, the ability to guarantee the therapeutic effect of allogeneic T-cells will be validated. Aim2. Demonstrate improved safety of AVM0703 and its ability to decrease risks of CRS associated with the injection of immunotherapeutic cells. The successful outcome of this project will provide the solid clinical foundation for the use of AVM0703 as preconditioning drug with current and future adoptive cellular therapies, to remove the need for chemotherapy. During an SBIR Phase II project, AVM will collaborate with Cancer Centers of Excellence for the generation of novel cancer cell therapies based on the use of AVM0703 to demonstrate their potential improved clinical outcomes. Ultimately, the tolerable regimen offered by AVM0703 might disrupt the future ?cancer concept? becoming a simple chronic disease treated with repeated administrations of non-toxic therapies.